3,4-diamino-1,2,5-thiadiazole-1-oxides having histamine H1 -antagonist activity

ABSTRACT

The invention relates to a class of 3,4-diamino-1,2,5-thiadiazole-1-oxides which have histamine H 1  -antagonist activity. A preferred compound of the invention is 3-[3-(5-bromo-3-methylpyrid-2-ylamino)-propylamino]-4-amino-1,2,5-thiadiazole-1-oxide.

This invention relates to certain pyridine derivatives, a process fortheir preparation, compositions containing them and their use ashistamine H₁ -antagonists.

Histamine, a physiologically active compound endogenous in mammals,exerts its action by interacting with certain sites called receptors.One type of receptor is known as a histamine H₁ -receptor (Ash andSchild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histamine atthese receptors are inhibited by drugs commonly called "antihistamines"(histamine H₁ -antagonists) a common example of which is mepyramine. Asecond type of histamine receptor is known as the H₂ -receptor (Black etal Nature 1972, 236, 385). The actions of histamine at these receptorsare not inhibited by mepyramine but are inhibited by burimamide.Compounds which inhibit the actions of histamine at histamine H₂-receptors are called histamine H₂ -antagonists.

Histamine H₁ -antagonists are useful in the treatment of diseases forexample, bronchial asthma, rhinitis, hayfever and allergic eczema, whosesymptoms are mediated by the effects of histamine at H₁ -receptors.

European Patent Application No. 0112707 discloses and claims "compoundsof formula (1): ##STR1## and pharmaceutically acceptable acid additionsalts thereof where R¹ is 2- or 3-pyridyl optionally bearing one or twosubstituents which are the same or different and which are C₁₋₄ alkyl,C₁₋₄ alkoxy, halogen, nitro, cyano or trifluoromethyl;

a is 2 to 4; and

R² is phenyl optionally bearing one or two substituents which are thesame or different and are halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy ora methylenedioxy group or is 3-pyridyl; N-oxo-3-pyridyl;6-methyl-3-pyridyl; N-oxo-6-methyl-3-pyridyl; 6-hydroxymethyl-3-pyridyl;4,6-dimethyl-3-pyridyl; N-oxo-4,6-dimethyl-3-pyridyl;6-hydroxymethyl-4-methyl-3-pyridyl; 5,6-dimethyl-3-pyridyl;N-oxo-5,6-dimethyl-3-pyridyl; 6-hydroxy-methyl-5-methyl-3-pyridyl;4-pyridyl or N-oxo-4-pyridyl."

These compounds are described as histamine H₁ -antagonists.

European Patent Application No. 0112142 discloses and claims "compoundsof formula (1): ##STR2## and pharmaceutically acceptable salts thereof;where R¹ is halogen, nitro, amino (or a pharmaceutically acceptablederivative of the amino group which is convertible in vivo into amino)or C₁₋₄ alkyl;

R² is halogen, nitro, amino (or a pharmaceutically acceptable derivativeof the amino group which is convertible in vivo into amino), C₁₋₄ alkyl,or C₃₋₄ alkoxy;

R³ is a C₁₋₃ alkylene group; and

R⁴ is inter alia a group of formula (5): ##STR3## where n is 0, 1 or 2and is R¹⁰ is hydrogen, C₁₋₆ alkyl, or optionally substituted phenyl orphenyl(C₁₋₆)alkyl (the substituents being one or more C₁₋₆ alkyl, orC₁₋₆ alkoxy groups or halogen atoms); or a methylenedioxy group oroptionally substituted pyridyl or pyridyl (C₁₋₆)alkyl where the optionalsubstituents are one or more C₁₋₆ alkyl or C₁₋₆ alkoxy groups or halogenatoms; or R⁴ is a group of formula (6): ##STR4## where R¹¹ is hydrogen,C₁₋₆ alkyl, optionally substituted phenyl or phenyl(C₁₋₆)alkyl, (thesubstituents being one or more C₁₋₆ alkyl or C₁₋₆ -alkoxy groups orhalogen atoms or a methylenedioxy group); optionally substituted pyridylor pyridyl (C₁₋₆)alkyl, the optional substituents being one or more C₁₋₆alkyl groups or C₁₋₆ alkoxy groups or halogen atoms; or a group offormula (7): ##STR5## where R¹² is hydrogen or C₁₋₆ alkyl, R¹⁵ ishydrogen or together with R¹² a fused benzene ring and m is 0, 1 or 2 ora group of formula (8): ##STR6## where R¹² is hydrogen or C₁₋₆ alkyl."

These compounds are also described as histamine H₁ -antagonists.

According to the present invention there are provided compounds offormula (1) : ##STR7## and pharmaceutically acceptable salts thereof;where A¹ is halogen, nitro, amino, C₁₋₆ alkyl or C₃₋₄ alkoxy;

A₂ is hydrogen, halogen, nitro, amino, C₁₋₆ alkyl or C₃₋₄ alkoxy;

m is 3 or 4;

A³ is hydrogen, C₁₋₆ alkyl or CH₂ A⁴ where

A⁴ is phenyl optionally bearing one or two substituents which are thesame or different and are C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or hydroxy,or a methylenedioxy group;

or is pyridyl optionally bearing one or two substituents which are thesame or different and are C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or hydroxy;

or is N-oxopyridyl optionally bearing a C₁₋₆ alkyl, C₁₋₆ alkoxy, orhalogen substituent;

or is pyrimidinyl optionally bearing one or two C₁₋₆ alkyl groups.

The compounds of this invention differ in structure from those describedin European Patent Application No. 0112707 in that the pyrimidine grouphas been replaced by a thiadiazolyl group.

The compounds of this invention differ in structure from those inEuropean Patent Application No. 0112142 in that the --CH₂ R³ CH₂ grouphas been replaced by an --NH(CH₂)_(m) group.

The compounds of this invention differ in activity from these knowncompounds because they have a relatively higher level of H₁ -antagonistactivity in vivo following oral administration as measured, for example,in the guinea pig bronchoconstriction assay described herein.

A¹ and A² can represent any one of the halogens, fluorine, chlorine,bromine or iodine.

Preferably A¹ is halogen, particularly bromine.

Examples of C₁₋₆ alkyl groups for A¹ and A² are methyl, ethyl, n-propyl,iso-propyl, n-butyl and t-butyl.

Examples of C₃₋₄ alkoxy groups for A¹ and A² are n-propoxy and n-butoxy.

Preferably A² is either C₁₋₆ alkyl or amino and particularly is methyl.

Preferably m is 3.

Examples of C₁₋₆ alkyl groups which A³ represents and C₁₋₆ alkylsubstituents for A³ and A⁴ are methyl, ethyl and n-propyl.

Examples of C₁₋₆ alkoxy substituents for A⁴ are methoxy, ethoxy andn-propoxy.

Examples of halogen substituents for A⁴ are fluorine, chlorine, bromineand iodine.

One class of compounds falling within the scope of this invention iswhere A³ is CH₂ A⁴ and A⁴ is phenyl optionally bearing one or twosubstituents which are the same or different and are C₁₋₆ alkyl, C₁₋₆alkoxy, halogen or hydroxy or a methylenedioxy group.

A particular example of the group CH₂ A⁴ 4-fluorobenzyl.

A further class of compounds falling within the scope of this inventionis where A⁴ is pyridyl optionally bearing one or two substituents whichare the same or different and are C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen orhydroxy.

Examples of optionally substituted pyridyl groups for A⁴ are optionallysubstituted pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl groups, andparticularly pyrid-3-yl, 6-methylpyrid-3-yl and 6-methoxypyrid-3-yl.

A particular example is pyrid-3-yl.

A further class of compounds within the scope of this invention is whereA⁴ is N-oxopyridyl optionally bearing a C₁₋₆ alkyl, C₁₋₆ alkoxy orhalogen substituent.

Preferably the pyridyl group is a 3- or 4-pyridyl group.

Examples of particular values for A⁴ in compounds of this class are6-methyl-N-oxopyrid-3-yl, 6-methoxy-N-oxopyrid-3-yl,6-chloro-N-oxopyrid-3-yl and especially N-oxopyrid-3-yl.

Preferably A⁴ is 4-fluorophenyl, pyrid-3-yl, pyrimid-4-yl,N-oxopyrid-3-yl or N-oxo-pyrid-4-yl.

Particular compounds within the scope of this invention are:

3-[4-(5-bromo-3-methylpyrid-2-ylamino)butylamino]-4-amino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-methylamino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(4-fluorobenzylamino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-pyrimid-4-ylmethylamino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-chloro-3-methylpyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide;

3-[3-(3,5-dibromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(pyrid-3-ylmethylamino)-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(N-oxopyrid-3-ylmethylamino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide;

3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(N-oxopyrid-4-ylmethylamino)-1,2,5-thiadiazole-1oxide;

and their pharmaceutically acceptable salts.

Compounds of formula (1) form pharmaceutically acceptable salts withpharmaceutically acceptable salt-forming acids. Examples ofpharmaceutically acceptable acid addition salts of compounds of formula(1) are those formed with hydrochloric, hydrobromic, sulphuric,phosphoric, acetic, citric, maleic, lactic, ascorbic, methanesulphonic,2-hydroxyethanesulphonic, toluene-4-sulphonic, ethanedisulphonic,ethanesulphonic and camphorsulphonic acids.

Compounds of formula (1) can be prepared by reacting a compound offormula (2): ##STR8## where A⁶ is a group A¹ or a protected amino groupand A⁷ is a group A² or a protected amino group where

A¹ and A² are as defined with reference to formula (1) and B¹ is a group--NH(CH₂)_(m) NH₂ where m is as defined with reference to formula (1) oris a group displaceable with amine, with a compound of formula (3):##STR9## where B² is a group displaceable with amine when B¹ is--NH(CH₂)_(m) NH₂, where m is defined with reference to formula (1), orB² is --NH(CH₂)_(m) NH₂ when B¹ is a group displaceable with amine; andB³ is a group displaceable with amine or a group NHA³, and where B³ is agroup displaceable with amine, reacting the product so obtained with anamine of the formula (4):

    A.sup.3 NH.sub.2                                           ( 4)

where A³ is as defined with reference to formula (1) and thereafter,where necessary, removing any protecting group from a protected aminogroup in the product so obtained; and optionally converting the compoundof formula (1) so obtained into a salt.

In the compounds of formula (2) the protecting group in the protectedamino group A⁶ or A⁷ can be any standard amino protecting group which isstable under the reaction conditions. For example it can be C₁₋₆-alkanoyl, benzyl or benzoyl. These protecting groups can be introducedand removed by standard methods.

The use of protecting groups is discussed in T. W. Greene, ProtectiveGroups in Organic Synthesis, 1981, John Wiley & Sons, IBSN0-471-05764-9.

Examples of leaving groups displaceable by amines are where B¹ ishalogen especially bromine and where B² or B³ are QS-, QSO-, QSO² -, orQO (Q being C₁₋₆ alkyl, aryl or aralkyl). Where B² or B³ are QO-, Q ispreferably methyl or phenyl. Preferably B² and B³ are QO- where Q ismethyl.

Compounds of formula (2) where B¹ is a group --NH(CH₂)_(m) NH₂ where mis as defined with reference to formula (1) can be prepared by reactinga compound of formula (2): ##STR10## where B¹ is a group displaceablewith amine, with an amine of formula (6):

    NH.sub.2 (CH.sub.2).sub.m NH.sub.2                         ( 6)

where m is as defined with reference to formula (1).

Compounds of formula (3) where B² is a group --NH(CH₂)_(m) NH₂ and B³ isa group --NHA³ can be prepared by reacting a compound of formula (3)where B² is a group displaceable with amine and B³ is a groupdisplaceable with amine or a group --NHA³ with a compound of formula(6):

    NH.sub.2 (CH.sub.2).sub.m NH.sub.2                         ( 6)

and where B³ is a group displaceable with amine reacting the product soobtained with a compound of formula (4) as previously defined.

It will be appreciated that each of the above mentioned reactionsinvolves either the displacement of a displaceable group from a pyridinering by an amine, or the displacement of a displaceable group from athiadiazole ring by an amine. These reactions can be carried out underconditions well known in the art in respect of analogous displacementreactions, see, for example, No. EP 0112704-A. Thus when the reactioninvolves the displacement of a displaceable group from a pyridine ring,e.g. the reaction of a compound of the formula (2) wherein B¹ is adisplaceable group, with a compound of the formula (6), it can becarried out at an elevated temperature in the absence of a solvent, forexample at a temperature of from 80° C. to 170° C., preferably from 120°C. to 140° C., or in a solvent at an elevated temperature, for examplethe reflux temperature of the reaction mixture. When the reactioninvolves the displacement of a displaceable group from a thiadiazolering, e.g. the reaction of a compound of the formula (2 ) wherein B¹ isa group NH(CH₂)_(m) NH₂ with a compound of the formula (3) wherein B² isa displaceable group, it can generally be carried out at moderate to lowtemperature, e.g. from 0° C. to room temperature. In the case of thedisplacement of a displaceable group B³ by a group A³ NH₂, in certaininstances, e.g. when A³ is 4-pyridylmethyl or N-oxopyridylmethyl, thereaction can advantageously be conducted at more elevated temperatures,for example at reflux temperature when A³ is N-oxopyridyl.

The choice of solvent is affected by the solubility characteristics ofthe reactants. Preferably the solvent is pyridine, a picoline or mixtureof picolines, a C₁₋₆ alkanol, 1,2-ethanediol, a high boiling alkoxyarylether, for example anisole, or a polar aprotic solvent, for exampledimethylformamide, dimethylacetamide, dimethylsulphoxide,hexamethylphosphoramide, or sulpholane. When the reaction involves thedisplacement of a displaceable group from a thiadiazole ring,particularly preferably the solvent is a C₁₋₆ alkanol, especiallymethanol and ethanol.

Compounds of formula (2) are known and can be made by analogy with knownprocesses as described, for example, in European Patent Application No.0112707.

Compounds of formula (3) are known or can be made by analogy with knownprocesses as described, for example, in U.K. Patent Application No.2067987A.

Compounds of formula (6) are known or can be made by analogy with knownprocesses.

The histamine H₁ -antagonist activity of the compounds of formula (1)can be demonstrated in vitro in the guinea pig ileum test. In this testan isolated portion of the guinea pig ileum is secured under tension(500 mg) between an anchorage and a transducer in a 10 ml tissue bathand immersed in magnesium free Tyrode solution with constant aeration ata temperature of 30° C. The output from the transducer is amplified. Theamplified output is in turn fed to a flat bed recorder. Measured amountsof histamine are added to the tissue bath so that the histamineconcentration increases step-wise until the force of the contractionreaches a maximum. The tissue bath is washed out and filled with freshmagnesium free Tyrode solution containing compound under test. Thesolution is left in contact with the tissue for 8 min. and measuredamounts of histamine are added again until a maximum contraction isrecorded. The assay is repeated with increasing concentrations of testcompound and the dose of histamine giving 50% of maximum contraction isnoted. A dose ratio (DR) was calculated by comparing the concentrationsof histamine required to produce 50% maximum response in the absence andin the presence of the antagonist. A plot of Log DR-1 against Log D (theconcentration of compound under test) is made and the point ofintersection with the Log (DR-1) ordinate is taken as the measure of theactivity (pA₂ value). All the compounds of the Examples below have pA₂values of 8 or above.

The activity of compounds of formula (1) as histamine H₁ -antagonistscan be demonstrated in vivo by the inhibition of histamine inducedbronchoconstriction. Guinea pigs of either sex are anaesthetised byintraperitoneal injection of sodium pentobarbitone, 90 mg/kg. Thetrachea is cannulated. The animal is respired artificially with a fixedvolume of air just adequate to inflate the lungs. The pressure needed toinflate the lungs is monitored from the respiratory system using a lowpressure transducer. Intravenous injection of histamine causesdose-dependent increases in the pressure to inflate the lungs reflectingthe bronchoconstrictor action of histamine. Responses to histamine canbe antagonised using histamine H₁ -receptor antagonists.

Dose-response curves to histamine are established at 20, 40, 80, 160 and320 nmols/kg. Antagonists are then administered by intravenous injectionand 5 minutes later a new histamine dose-response curve is establishedincreasing the doses of histamine as necessary. The effect of theantagonist can be quantified by the displacement, to the right, of thehistamine dose-response curve, expressed as a dose-ratio. A series ofdoses of antagonists may be given to each animal allowing calculation ofdose-ratios for each dose of antagonist.

For all the compounds exemplified below, the dose of compound requiredto give a dose ratio of 11 is in the range 0.033-1.1 μmole/kg, themajority of them requiring a dose of less than 0.4 μmole/kg.

In order to use the compounds of the invention as histamine H₁-antagonists, they can be formulated as pharmaceutical compositions inaccordance with standard pharmaceutical procedure.

The invention also includes pharmaceutical compositions comprising acompound of formula (1) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

Compounds of formula (1) and their pharmaceutically acceptable salts canbe administered topically or systemically.

Topical formulations for administration to the skin include lotions andcreams. Topical formulations for administration to the respiratory tractinclude solutions for application via a nebulizer or as an aerosol, or amicrofine insufflatable powder. The active ingredient in aninsufflatable powder has a small particle size i.e. less than 50 micronsand preferably less than 10 microns. The active material is co-presentedwith a solid carrier for example lactose which has a particle size ofless than 50 microns.

Systemic administration can be achieved by rectal, oral or parenteraladministration. A typical suppository formulation comprises the activecompound with a binding agent and/or lubricating agent for examplegelatine or cocoa butter or other low melting vegetable waxes or fats.Typical parenteral compositions consist of a solution or suspension ofthe active material in a sterile aqueous carrier or parenterallyacceptable oil.

Compounds of formula (1) which are active when given orally can beformulated as syrups, tablets, capsules and lozenges. A syrupformulation generally consists of a suspension or solution of thecompound in a liquid carrier for example ethanol, glycerine or waterwith a flavouring or colouring agent. Where the composition is in theform of a capsule, the solid in granular form optionally with a bindingagent is encased in a gelatin shell. Where the composition is in theform of a tablet, any suitable pharmaceutical carrier routinely used forpreparing solid formulations can be used. Examples of such carriersinclude magnesium stearate, starch, lactose, glucose, sucrose, andcellulose. Preferably the composition is in unit dose form for example atablet, capsule or metered aerosol so that the patient may administer tohimself a single dose.

Where appropriate, small amounts of bronchodilators and anti-asthmaticsfor example sympathomimetic amines particularly isoprenaline,isoetharine, salbutamol, phenylephrine and ephedrine; xanthinederivatives particularly theophylline and aminophylline; andcorticosteroids particularly prednisolone and adrenal stimulantsparticularly ACTH can be included. As in common practice, thecompositions will usually be accompanied by written or printeddirections for use in the medical treatment concerned, in this case as ahistamine H₁ -antagonist for treatment of, for example, asthma, hayfeverrhinitis or allergic eczema.

Each dosage unit for oral administration contains preferably from 5 to200 mg of a compound of formula (1) or a pharmaceutically acceptablesalt thereof calculated as the free base.

The pharmaceutical compositions of the invention will normally beadministered to a man for the treatment of rhinitis, hayfever, bronchialasthma or allergic eczema. An adult patient will receive an oral dose ofbetween 15 mg and 400 mg and preferably between 15 mg and 200 mg or anintravenous, subcutaneous or intramuscular dose of between 1 mg and 50mg, and preferably between 1 mg and 10 mg of a compound of formula (1)or a pharmaceutically acceptable salt thereof calculated as the freebase, the composition being administered 1 to 4 times per day.

The following Examples illustrate the invention.

EXAMPLE 1

3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (0.713 g) was addeddropwise to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.639 g) in methanol (25 ml) atroom temperature. After 4 hours at room temperature, methanolic ammonia(25 ml) was added at 0°-5° C. with stirring, the mixture allowed tostand overnight, then evaporated in vacuo. The residue waschromatographed on silica in 10% CH₃ OH/CHCl₃. The product wascrystallised from ethanol to give4-amino-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide(0.322 g, 32%) m.p. 204°-205° C.

EXAMPLE 2

4-(5-Bromo-3-methylpyrid-2-ylamino)butylamine (0.7 g) in methanol wasreacted with 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.44 g) overnightat room temperature. Methanolic ammonia (25 ml) was added and thereaction mixture was stirred for 2 hours. After evaporation, the residuewas recrystallised from a mixture of acetonitrile and ether to yield4-amino-3-[4-(5-bromo-3-methylpyrid-2-ylamino)-butylamino]-1,2,5-thiadiazole-1-oxide(0.45 g, 45%) m.p. 212°-214° C. dec.

EXAMPLE 3

Substituting 3-(5-chloro-3-methylpyrid-2-ylamino)-propylamine (1.10 g)for 3-(5-bromo-3-methylpyrid-2-yl-amino)propylamine, using correspondingmolar proportions of reagents and conditions analogous to thosedescribed in Example 1 gave, after chromatography on silica, 10% CH₃OH/CHCl₃ and recrystallisation from propan-2-ol/methanol,4-amino-3-[3-(5-chloro-3-methyl-pyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide(0.525 g, 30%), m.p. 200°-202° C.

EXAMPLE 4

Substituting 3-(3,5-dibromopyrid-2-ylamino)propylamine (0.84 g) for3-(5-bromo-3-methylpyrid-2-ylamino)-propylamine, using correspondingmolar proportions of reagents and conditions analogous to thosedescribed in Example 1 gave, after chromatography on silica in 10% CH₃OH/CHCl₃ and recrystallisation from propan-2-ol/methanol,4-amino-3-[3-(3,5-dibromopyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide (0.18 g, 16%) m.p. 197°-203° C.(decomp.)

EXAMPLE 5

A solution of 3-(5-bromopyrid-2-ylamino)propylamine (1 g) and3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.71 g) was stirred in methanolfor 3 hours. Methanol saturated with ammonia (10 ml) was added and thesolution was stirred for 18 hours, concentrated in vacuo and the residuewas chromatographed on silica eluted with 10% v:v methanol in chloroformfollowed by recrystallisation from methanol to give3-[3-(5-bromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide(0.63 g), m.p. 215°-216° C.

EXAMPLE 6

3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (1.0 g) was reacted with3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.65 g) in methanol for 6hours. Methylamine in ethanol (15 ml) was added and stirred for 2 hours.After evaporation the residue was recrystallised from a mixture ofacetonitrile and ether and then from ethanol to yield4-methylamino-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide(0.37 g, 25%), m.p. 211°-212° C.

EXAMPLE 7

3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (1.0 g) was reacted with3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.65 g) in methanol overnight.p-Fluorobenzylamine (0.51 g) was added and the reaction mixture wasstirred for 2 hours. The product was filtered off and recrystallisedfrom ethanol to yield4-(p-fluorobenzylamino)-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide(0.77 g, 40%) m.p. 125°-126° C.

EXAMPLE 8

Substituting 3-aminomethylpyridine (5 ml) for methanolic ammonia, usingcorresponding molar proportions and conditions analogous to thosedescribed in Example 1 gave, after chromatography on silica in 10% CH₃OH/CHCl₃ and recrystallisation from propan-2-ol,3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(pyrid-3-ylmethylamino)-1,2,5-thiadiazole-1-oxide(0.533 g, 29%), m.p. 162°-165° C.

EXAMPLE 9

3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (0.7 g) was addeddropwise to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.46 g) in methanol (20 ml) atroom temperature.

After 21 hours, 4-aminomethylpyrimidine (0.37 g) was added and thereaction mixture was stirred for 5 hours. After two days standing, afurther addition of 4-aminomethylpyrimidine (0.05 g) was made and thestirred reaction was heated at 30°-50° C. for 3 hours. The reactionmixture was then evaporated in vacuo. The residue (1.4 g) waschromatographed on silica in 10% MeOH/CHCl₃, and then crystallised fromethanol/acetonitrile to give3-[3-(5-bromo-3-methylpyrid-2-ylamino)-propylamino]-4-(pyrimidin-4-ylmethylamino)-1,2,5-thiadiazole-1-oxide(0.84 g, 65%), m.p. 171°-172° C.

EXAMPLE 10

3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (0.7 g) was added to asolution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.46 g) in methanol(20 ml) at room temperature.

After 3 hours stirring 3-aminomethylpyridine-N-oxide (0.48 g) was added.The reaction mixture was concentrated to ca. 10 ml volume and refluxedfor 2 hours and then concentrated in vacuo. The residue (1.6 g) waschromatographed on silica in 20% MeOH/CHCl₃, and then crystallised frommethanol to give3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-4-(N-oxopyrid-3-ylmethylamino-1,2,5-thiadiazole-1-oxide(0.36 g, 27%), m.p. 202° C. (decomposition).

EXAMPLE 11

(a) To 4-aminomethylpyridine (15 g) cooled to 0° C. was added, withstirring, acetic anhydride (15 ml). After 30 min., the dark viscous oilwas taken up in chloroform and extracted with 5% sodium bicarbonatesolution (3×). The aqueous extracts were adjusted to ca. pH 8, saturatedwith sodium chloride and extracted with chloroform. Concentrationafforded 4-pyridylmethylacetamide (9.60 g, 50%) as a yellow solid. Tothe latter (6.9 g) in dichloromethane (100 ml) was addedm-chloroperbenzoic acid (10.2 g) in dichloromethane (50 ml) at 0° C.over 0.5 hr. The mixture was left overnight at room temperature andconcentrated. The residue was chromatographed (silica, 10% rising to 25%CH₃ OH/CHCl₃) to give pyrid-N-oxo-4-ylmethylacetamide (7.17 g, 93%) asan off-white solid. The latter (5.8 g) was heated under reflux with 95%ethanol (20 ml) and concentrated hydrochloric acid (20 ml) for 1.5 hr.Cooling afforded 4-aminomethylpyridine-N-oxide dihydrochloride (3.85 g,52%) as a precipitate; m.p. (from ethanol) 176°-178° C.

(b) 3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (0.7 g) was reactedwith 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.46 g) in methanol (20ml) for 3 hours, followed by the addition of a suspension of4-aminomethylpyridine N-oxide dihydrochloride (0.75 g) in sodiummethoxide (0.16 g sodium in 20 ml methanol). The stirred mixture wasconcentrated to approximately 10 ml and was then heated under reflux for5 hours. After cooling overnight the product was filtered off and washedsparingly with methanol, water and again methanol. Recrystallisationfrom methanol gave3-[3-(5-bromo-3-methylpyrid-2-ylamino)-propylamino]-4-(N-oxopyrid-4-ylmethylamino)-1,2,5-thiadiazole-1-oxide(0.7 g) m.p. 202° C. (decomposition).

EXAMPLE 12

A pharmaceutical composition for oral administration is preparedcontaining

    ______________________________________                                                                % by weight                                           ______________________________________                                                  4-Amino-3-[3-(5-bromo-3-methylpyrid-                                                                  55                                                    2-ylamino)propylamino]-1,2,5-thiadiazole-                           A         1-oxide                                                                       Dibasic calcium phosphate dihydrate                                                                   20                                                    Approved coloring agent 0.5                                                   Polyvinylpyrrolidone    4.0                                                   Microcrystalline Cellulose                                                                            8.0                                                   Maize Starch            8.0                                         B         Sodium glycollate       4.0                                                   Magnesium Stearate      0.5                                         ______________________________________                                    

by mixing together the ingredients A (substituting lactose ormicrocrystalline cellulose for dibasic calcium phosphate dihydrate ifdesired), adding a concentrated solution of polyvinylpyrrolidone andgranulating, drying and screening the dried granules; adding theingredients B to the dried granules and compressing the mixture intotablets containing 5 mg, 25 mg or 50 mg of the free base.

EXAMPLE 13

A pharmaceutical composition for injectable administration is preparedby forming a solution of4-amino-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxidein sterile water to give a 1 to 5% w/w solution. The solution isclarified by filtration and filled into vials which are sealed andsterilised. A suitable vial contains 2 ml of the solution.

What is claimed is:
 1. A compound of formula (1): ##STR11## or apharmaceutically acceptable salt thereof; where A¹ is halogen, nitro,amino, C₁₋₆ alkyl or C₃₋₄ alkoxy;A² is hydrogen, halogen, nitro, amino,C₁₋₆ alkyl or C₃₋₄ alkoxy; m is 3 or 4; A³ is hydrogen, C₁₋₆ alkyl orCH₂ A⁴ where A⁴ is phenyl unsubstituted or substituted with one or twosubstituents which are the same of different and are C₁₋₆ alkyl, C₁₋₆-alkoxy, halogen or hydroxy, or a methylenedioxy group;or is pyridylunsubstituted or substituted with one or two substituents which are thesame or different and are C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or hydroxy;or is N-oxopyridyl unsubstituted or substituted with a C₁₋₆ alkyl, C₁₋₆alkoxy, or halogen substituent; or is pyrimidinyl unsubstituted orsubstituted with one or two C₁₋₆ alkyl groups.
 2. A compound as claimedin claim 1 where A¹ is halogen.
 3. A compound as claimed in claim 2where A¹ is bromine.
 4. A compound as claimed in claim 1 where A² isC₁₋₆ alkyl.
 5. A compound as claimed in claim 4 where A² is methyl.
 6. Acompound as claimed in claim 1 where A³ is hydrogen.
 7. A compound asclaimed in claim 1 where A⁴ is phenyl unsubstituted or substituted withone or two substituents which are the same or different and are C₁₋₆alkyl, C₁₋₆ alkoxy, halogen or hydroxy or a methylenedioxy group.
 8. Acompound as claimed in claim 7 where A⁴ is 4-fluorophenyl.
 9. A compoundas claimed in claim 1 where A⁴ is pyridyl unsubstituted or substitutedwith one or two substituents which are the same or different and areC₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or hydroxy.
 10. A compound as claimedin claim 9 where A⁴ is pyrid-3-yl.
 11. A compound as claimed in claim 1where A⁴ is N-oxopyridyl unsubstituted or substituted with a C₁₋₆ alkyl,C₁₋₆ alkoxy or halogen substituent.
 12. A compound as claimed in claim11 where A⁴ is N-oxopyrid-3-yl.
 13. A compound as claimed in claim 1where A⁴ is a phenyl unsubstituted or substituted with one or twosubstituents which are the same or different and are C₁₋₆ alkyl, C₁₋₆alkoxy, halogen or hydroxy, or a methylenedioxy group;or is pyridylunsubstituted or substituted with one or two substituents which are thesame or different and are C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or hydroxy;or is N-oxopyridyl unsubstituted or substituted with a C₁₋₆ alkyl, C₁₋₆alkoxy, or halogen substituent; or is pyrimidinyl unsubstituted orsubstituted with one or two C₁₋₆ alkyl groups.
 14. A compound as claimedin claim 13 where A⁴ is pyrimidin-4-yl. 15.3-[4-(5-Bromo-3-methylpyrid-2-ylamino)butylamino]4-amino-1,2,5-thiadiazole-1-oxide.16.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide.17.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-methylamino-1,2,5-thiadiazole-1-oxide.18.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-(4-fluorobenzylamino-1,2,5-thiadiazole-1-oxide.19.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-pyrimid-4-ylmethylamino-1,2,5-thiadiazole-1-oxide.20.3-[3-(5-Chloro-3-methylpyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide.21.3-[3-(3,5-Dibromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide.22.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-(pyrid-3-ylmethylamino)-1,2,5-thiadiazole-1-oxide.23.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-(N-oxopyrid-3-ylmethylamino)-1,2,5-thiadiazole-1-oxide.24.3-[3-(5-Bromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide.25.3-[3-(5-Bromo-3-methylpyrid-2-ylamino)propylamino]-4-(N-oxopyrid-4-ylmethylamino)-1,2,5-thiadiazole-1-oxide.26. A pharmaceutical composition having histamine H₁ antagonistactivity, which comprises, in an effective amount to produce suchactivity, a compound as claimed in claim 1 and a pharmaceuticallyacceptable carrier.
 27. A method of blocking histamine H₁ -receptorswhich comprises administering to a subject a non-toxic effective amountto block said receptors of a compound according to claim 1.